The incidence of non-melanoma skin cancer (NMSC) is increasing rapidly, and further increases are expected. A small proportion of these basal and squamous cell carcinomas of the skin exhibit an aggressive phenotype, characterized by multiple recurrences, size more then 2 cm, invasion of muscle, cartilage, bone, or nerves, or lymph node metastasis. The State of Texas has a high incidence of skin cancer and an unusually high death rate from NMSC. Because of its geographic location and referral patterns, the University of Texas M. D. Anderson Cancer Center treats a large number of highly aggressive NMSC; in fact, nearly half of the approximately 100 new cases of skin cancer seen annually in the Department of Head and Neck Surgery exhibit aggressive behavior and are difficult to control by surgery and radiation. Progress toward reducing the incidence of and morbidity and mortality from NMSC requires a 3-pronged approach; Identification of the etiologic and genetic factors that contribute to skin cancer induction; determination of the host and tumor characteristics associated with skin cancer progressions; and development of new approaches for the treatment of highly aggressive NMSC. The specific aims of this Program are therefore, to (1) develop an understanding of the molecular events leading to skin cancer development; (2) ascertain athe role of UV radiation in the development of NMSC, including those with aggressive behavior, (3) assess the contribution of various mechanisms to progression of NMSC; (4) reduce morbidity and mortality and improve the quality of life of patients with aggressive skin cancer. These goals will be addressed by 16 Key Program Investigators in laboratory and clinical investigations on the role of p53 in UV carcinogenesis and immunosuppression (Project 1); regulation of apoptosis in skin cancer development (Project 2); DNA repair and chromosome instability in skin cancers (Project 3); and adjuvant biotherapy of aggressive skin cancers with 13-cis retinoic acid and interferon-alpha (Project 5). These studies will be coordinated and supported by cores devoted to collection of clinical, pathological, molecular, and epidemiological data and procurement, maintenance, processing, and distribution of clinical samples and biostatistical analysis and integration of laboratory and clinical data. These efforts will be supported by 16 collaborators/co-investigators and 8 Program Advisors. The Program Project will provide information on the etiology, biology, pathogenesis, and mechanisms of induction of NMSC and generate valuable clinical and epidemiological databases.